Abstract

Background

Molecular diagnostics can resolve locus heterogeneity underlying clinical phenotypes
that may otherwise be co-assigned as a specific syndrome based on shared clinical
features, and can associate phenotypically diverse diseases to a single locus through
allelic affinity. Here we describe an apparently novel syndrome, likely caused by
de novo truncating mutations in ASXL3, which shares characteristics with Bohring-Opitz syndrome, a disease associated with
de novo truncating mutations in ASXL1.

Methods

We used whole-genome and whole-exome sequencing to interrogate the genomes of four
subjects with an undiagnosed syndrome.

Results

Using genome-wide sequencing, we identified heterozygous, de novo truncating mutations in ASXL3, a transcriptional repressor related to ASXL1, in four unrelated probands. We found that these probands shared similar phenotypes,
including severe feeding difficulties, failure to thrive, and neurologic abnormalities
with significant developmental delay. Further, they showed less phenotypic overlap
with patients who had de novo truncating mutations in ASXL1.

Conclusion

We have identified truncating mutations in ASXL3 as the likely cause of a novel syndrome with phenotypic overlap with Bohring-Opitz
syndrome.